insulin-like growth factor I (IGF-I) is a peptide present in the plasma and other body fluids. In its mature processed form it comprises 70 amino acids and can stimulate growth of a wide range of cell types. Human IGF-I have been cloned and its cDNA sequence can be found in Jansen et al, Nature, 1993 (reference 11 below). The cDNA sequence encodes a precursor (also known as the D-chain), a mature 70 amino acid comprising the B, C and A regions respectively, and a C-terminal region which is termed the E-peptide. Recently, it has been found that the E-peptide can exist in different isoforms. This arises as a result of alternative splicing at the mRNA level. Chew et al report the existence of three alternatively spliced T-terminal regions of human IGF-I. One of the isoforms produced is as a result of splicing between exons 4, 5 and 6 of the gene and this predicts a prepro-IGF-I molecule of 158 amino acids including a C-terminal peptide, the Ec peptide of 24 amino acids in length. This Ec peptide appears to correspond to the Eb peptide found in rat IGF-I.
IGF-I has been proposed for use of a number of disorders relating to muscle atrophy and related conditions. For example, WO92/11865 proposes the use of human IGF-I for the prevention or treatment of cardiac disorders and for the promotion of cardiac muscle protein synthesis, for prevention or treatment of cardiomyophthies, acute heart failure or acute insult including myocarditis or myocardial infarction and for improving cardiac output by increasing heart/volume. WO95/13290 relates to the use of IGF-I for treating muscular disorders such as muscular dystrophy and related progressive skeletal muscle weakness and wasting.
W093/09236 teaches methods of gene therapy using myogenic vector systems comprising promoters suitable for use in muscle cells. Such vectors may be introduced into a human patient for the treatment of muscle atrophy in ageing humans, muscle atrophy induced by spinal cord injuries or neuromuscular diseases.
A difficulty with the use of IGF-I is that this peptide is responsible for a wide range of effects within the human body. Although IGF-I is produced in muscle cells it is also produced in the liver from where it circulates and is involved in regulating metabolism. Administration of IGF-I may thus induce side-effects including hypoglycaemia.
De Vol et al (1990), Am. J. Physiol. 259, E89-E95) report that IGF-I expression is elevated during work-induced skeletal muscle growth.